A vaccine may contain a wide variety of different antigens ranging from whole-killed organisms such as inactivated viruses or bacteria, fungi, protozoa, or cancer cells to sub-fractions of these organisms/tissues, proteins or peptides. Antigens can be recognized by the immune system in the form of proteins or peptides and can contain polysaccharides and/or lipids. Short peptides can be used since cytotoxic T cells recognize antigens in the form of short, usually about 8-16 amino acids long, peptides in conjunction with major histocompatibility complex (MHC).
Peptides are increasingly important in vaccine design. It has been shown that co-injection of a mixture of poly-L-arginine or poly-L-lysine together with an appropriate peptide as a vaccine protects animals from tumor growth in mouse models. (Buschle et al., Gene Ther Mol Biol (1998) 1:309-321 and Schmidt et al., PNAS (1997) 94:3262-3267). This vaccine is able to induce high numbers of antigen/peptide-specific T cells.
In order to induce antigen-specific T cells, peptides must be taken up by antigen presenting cells (APCs). APCs induce an immune cascade which eventually leads to the induction of antigen-specific immune effector cells such as cytotoxic T cells. However, it a well recognized problem in the art that many peptides defining antigenic regions of medically important pathogens fail to provide a sufficient immune response in vivo.
Essentially, any peptide that is able to bind an MHC molecule may function as a T cell epitope. The presence of a T cell with a corresponding T cell receptor (TCR) and the absence of tolerance for this particular epitope are prerequisites for the induction of an in vitro or in vivo T cell response. T helper cells orchestrate the effector function of CTLs in anti-tumor immunity. T helper cell epitopes that trigger a T helper cell response of the TH1 type support effector functions of CD8+ killer T cells, which include cytotoxic functions directed against tumor cells displaying tumor-associated peptide/MHC complexes on the cell surface. In this way, tumor-associated T helper cell peptide epitopes, alone or in combination with other tumor-associated peptides can serve as pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses.
Adjuvants must trigger immune cascades that involve all cells of the immune system that are necessary in order to obtain a sustained, antigen-specific immune response. Adjuvants primarily act on antigen presenting cells (APCs) such as dendritic cells (DC). These cells are normally the first cells to encounter an antigen followed by presentation of processed or unmodified antigen to immune effector cells. While intermediate cell types may be involved, only effector cells with the appropriate specificity are activated in a protective immune response. Adjuvants may locally retain antigens and co-injected other factors as well as act as chemoattractants for other immune cells. Adjuvants may also act locally and/or systemically as a stimulating agent for the immune system.
Polyinosinic-polycytidylic acid (poly IC) is a potent interferon I inducer. Poly-IC is a synthetic double stranded nucleic acid that functions as an immune adjuvant, stimulating pattern recognition receptors (PRRs), such as the toll-like receptor-3 (TLR3) and cytoplasmic helicases (RIG-I-like receptors) that are present on specialized antigen-presenting cells such as dendritic cells (DCs). In addition, Poly-IC is able to target the associated peptide antigen to DCs via scavenger receptors (SRs). Due to its protective effects in a number of different animal species against a broad spectrum of both RNA and DNA viruses, poly IC is often used in models of viral infections. The changes that occur in response to poly IC are thought to be representative of changes that occur in response to a variety of different viruses. Poly IC is known to stimulate macrophages to produce cytokines such as IL-1a and IL-12. It is also known as a potent NK cell stimulator and promotes Th-1 specific immune responses. Poly IC also induces stable maturation of in vitro cultured dendritic cells and that such dendritic cells are potent T cell stimulators in vitro. Due to these attributes, poly IC has been widely used as an immunomodulator in several clinical studies.
The prior art has failed to adequately address the problem of developing an effective vaccine which allows effective delivery of a specific antigen to the immune system in order to activate antigen-specific T cells against that specific antigen in a subject.